LATANOPROST/TIMOLOL ZENTIVA 50 µg/5 mg per ml Eye drops solution 3Bottle/2,5ml

Eye drops in solution.

Colourless, odourless and clear solution.

pH between 5,5 and 6,5.

Osmolality between 260 and 320 mOsmol/kg.

Latanoprost................................................................................................................................50 micrograms

Timolol..........................................................................................................................................................5,00 mg

As timolol maleate...........................................................................................................6,83 mg

For 1 mL of eye drops in solution

Excipient with known effect: Benzalkonium chloride solution at 50 %: 0,412 mg/mL, sodium dihydrogen phosphate monohydrate at 6,390 mg/mL and anhydrous disodium phosphate at 2,890 mg/mL (phosphate buffers).

Excipients:

LATANOPROST/TIMOLOL ZENTIVA is indicated in adults (including elderly persons) for the reduction of intraocular pressure (IOP) in patients with open-angle glaucoma and ocular hypertension who show an inadequate response to topically administered beta-blockers or prostaglandin analogues.

Dosage

AAdults (including the elderly)

The recommended dose is one drop in the affected eye(s) once daily.

If a dose is missed, treatment should continue as normal with the next instillation. The dose should not exceed one drop per day in the affected eye(s).

Paediatric population

The efficacy and tolerability of latanoprost/timolol have not been established in children and adolescents.

Method of administration

Contact lenses must be removed before instillation of the eye drops and may be reinserted 15 minutes after (see section Warnings and precautions).

When several topical ophthalmic products are used concomitantly, the instillations of the different products must be separated by at least five minutes.

Nasolacrimal occlusion or closure of the eyelids for 2 minutes reduces systemic absorption. This results in a reduction of systemic adverse effects and an increase in local activity.

The latanoprost/timolol combination is contraindicated in patients presenting with:

• Hypersensitivity to one of the active substances or to one of the excipients listed in the section Composition
• Conditions associated with bronchial hyperreactivity, in particular asthma or a history of asthma, and severe chronic obstructive pulmonary disease.
• Sinus bradycardia, sick sinus syndrome, sino-atrial block, second- or third-degree atrioventricular block not controlled by a pacemaker, confirmed heart failure, cardiogenic shock.

Systemic effects

Like any topically applied ophthalmic agent, LATANOPROST/TIMOLOL ZENTIVA has systemic absorption. Due to the presence of timolol, a beta-adrenergic component, cardiovascular and pulmonary adverse reactions, and other adverse reactions similar to those seen with systemically administered beta-adrenergic blocking agents, may occur.

The frequency of systemic adverse reactions after topical ophthalmic administration is lower than after systemic administration. To reduce systemic absorption, see section Dosage and administration.

Cardiac disorders

In patients with cardiovascular disease (coronary artery disease, Prinzmetal's angina, heart failure) and hypotension, treatment with beta-blockers should be carefully evaluated and treatment with other medicinal products should be considered. In these patients, monitoring should be carried out to look for signs of worsening of these conditions or adverse reactions.

Due to their negative dromotropic effect, beta-blockers should only be prescribed with caution to patients with first-degree heart block.

After administration of timolol, cardiac effects and, rarely, deaths in association with heart failure have been reported.

Vascular disorders

Patients suffering from severe disorders of peripheral circulation (i.e. the severe form of the disease or Raynaud's syndrome) should be treated with caution.

Respiratory disorders

In asthmatic patients, respiratory manifestations including death due to bronchospasm have been reported following administration of certain ophthalmic beta-blockers. LATANOPROST/TIMOLOL ZENTIVA should be administered with caution in patients with moderate to severe chronic obstructive pulmonary disease (COPD) and only if the potential benefit appears to outweigh the potential risk.

Hypoglycaemia/Diabetes

Beta-blockers should be administered with caution in patients prone to spontaneous hypoglycaemia or in patients with unstable diabetes, as beta-blockers may mask the signs of acute hypoglycaemia.

Hyperthyroidism

Beta-blockers may also mask the signs of hyperthyroidism.

Corneal diseases

Ophthalmic beta-blockers may cause ocular dryness. Patients with corneal diseases should be treated with caution.

Other beta-blocking agents

The effect on intraocular pressure or the known effects of systemic beta-blockers may be potentiated when timolol is administered to patients already receiving an oral beta-blocker. The response of these patients should be closely monitored.

The topical use of 2 beta-blockers is not recommended (see section Interactions).

Concomitant treatment

Interactions of timolol with other medicinal products have been described (see section Interactions).

Other prostaglandin analogues

The concomitant use of two or more beta-blockers topical prostaglandins, prostaglandin analogues, or prostaglandin derivatives is not recommended (see section Interactions).

Anaphylactic reactions

Patients treated with beta-blockers who have a history of atopy or of severe anaphylactic reaction to various allergens may be more reactive to repeated administration of such allergens and may not respond to the doses of adrenaline usually used to treat anaphylactic reactions.

Choroidal detachment

Choroidal detachments have been observed after glaucoma filtration surgery with the administration of treatments that reduce aqueous humor secretion (e.g., timolol, acetazolamide).

Surgical anesthesia

Beta-blockers used in ophthalmology may block the effects of systemic beta-agonists such as adrenaline. The anaesthetist must be informed when the patient is receiving timolol.

Change in iris pigmentation

Latanoprost may gradually change eye color by increasing the amount of brown pigment in the iris. This pigmentation was also observed (with photographic control) in 16 to 20 % of patients treated for one year with the latanoprost + timolol combination (50 micrograms/ml + 5 mg/ml); in particular in patients with multicolored irises: green-brown, yellow-brown or blue/gray-brown. It is due to an increase in the melanin content of the melanocytes in the iris stroma. Generally, in the affected eyes, the brown pigmentation surrounding the pupil extends concentrically toward the periphery, the iris potentially becoming partially or completely browner. Clinical studies show that after two years of treatment, these color changes were rarely observed in patients with uniformly colored eyes, blue, gray, green or brown.

Changes in iris colour develop slowly and may go unnoticed for months or even years. This effect has not been associated with any symptoms or pathological changes.

After treatment discontinuation, no further progression of brown iris pigmentation was observed, but the colour change may be permanent.

Neither iris naevi nor ephelides were affected by treatment.

No accumulation of pigment in the trabecular meshwork or at other points in the anterior chamber was observed. However, patients should be examined regularly and, depending on the clinical context of the patient, treatment may be discontinued in case of increased iris pigmentation.

Before starting treatment, patients should be informed of the risk of eye colour change. Unilateral treatment may result in permanent heterochromia.

Changes in eyelids and eyelashes

A darker coloration of the eyelid skin, which may be reversible, has been reported in association with the use of latanoprost.

Latanoprost may gradually alter the eyelashes and vellus hair of the treated eye; these changes include an increase in length, thickness, pigmentation and number of eyelashes or hairs, and inadequate orientation of the eyelashes. Eyelash changes are reversible upon discontinuation of treatment.

Glaucoma

There is currently no documented experience on the efficacy of latanoprost in inflammatory, neovascular or chronic angle-closure glaucoma, in open-angle glaucoma of the pseudophakic patient, or in pigmentary glaucoma.

Latanoprost has little or no effect on the pupil. However, there is currently no documented experience in acute angle-closure glaucoma attacks. Therefore, in the absence of additional data, it is recommended that LATANOPROST/TIMOLOL be used with caution in these situations.

Herpetic keratitis

Latanoprost should be used with caution in patients with a history of herpetic keratitis, and its use should be avoided in cases of active herpes simplex keratitis and in patients with a history of recurrent herpetic keratitis specifically associated with prostaglandin analogues.

Macular oedema

Cases of macular edema, including cystoid macular edema, have been reported during treatment with latanoprost. These were mainly in aphakic or pseudophakic patients with posterior capsular rupture or in patients with known risk factors for macular edema. Therefore, the latanoprost/timolol combination should be used with caution in these patients.

Benzalkonium chloride

This medicine contains 0,412 mg of benzalkonium chloride at 50% in each ml. Benzalkonium chloride is known to cause eye irritation and dry eye syndrome symptoms, and may affect the tear film and the corneal surface. It should be used with caution in patients with dry eye and those at risk of corneal damage. Patients should be monitored during prolonged use.

Use of contact lenses

Benzalkonium chloride may be absorbed by contact lenses and change their color. Contact lenses should be removed before instillation of the latanoprost/timolol combination and may be reinserted 15 minutes after (see section Dosage and administration).

Phosphate buffers

LATANOPROS/TIMOLOL ZENTIVA contains sodium dihydrogen phosphate monohydrate and anhydrous disodium phosphate as buffering agents; these excipients may cause the undesirable side effect of corneal calcification, please refer to the section Adverse effects (Undesirable effects) for more information.

No specific drug interaction studies have been carried out with the latanoprost/timolol combination.

Paradoxical increases in intraocular pressure have been reported following concomitant ophthalmic administration of two prostaglandin analogues. Therefore, the use of two or more prostaglandins, prostaglandin analogues, or prostaglandin derivatives is not recommended.

An additive effect, resulting in hypotension and/or bradycardia, may be observed when ophthalmic beta-blocker solution is administered concomitantly with calcium channel inhibitors, beta-adrenergic blocking agents, antiarrhythmics (notably amiodarone), digitalis glycosides, parasympathomimetics, and systemically administered guanethidine.

Potentiation of systemic beta-blocking effects (for example: decreased heart rate, depression) has been reported when CYP2D6 inhibitor treatments (for example: quinidine, fluoxetine and paroxetine) are combined with timolol.

The effect on intraocular pressure or the known effects of systemic beta-blockers may be potentiated when the latanoprost/timolol combination is administered to patients already receiving an oral beta-blocker, and the use of two or more topical beta-blocking agents is not recommended.

Mydriasis has occasionally been reported when ophthalmic beta-blockers and adrenaline (epinephrine) have been used concomitantly.

The rebound hypertensive surge occurring on abrupt withdrawal of clonidine may be increased when beta-blockers are administered.

Beta-blockers may increase the hypoglycaemic effect of antidiabetic agents. They may mask the signs and symptoms of hypoglycaemia (see section Warnings and precautions).

Pregnancy

Latanoprost

There are no data on the use of latanoprost in pregnant women. In animals, studies have shown toxicity on reproductive functions (see section Preclinical safety). The potential risk in humans is not known.

Timolol

There are no adequate data on the use of timolol in pregnant women. Timolol should not be used during pregnancy unless clearly necessary. To reduce systemic absorption, see section Dosage and administration.

Epidemiological studies have not revealed a malformative effect but demonstrate a risk of intrauterine growth retardation when beta-blockers are administered orally. In addition, signs and symptoms of a beta-blocker effect (for example: bradycardia, hypotension, respiratory distress and hypoglycaemia) have been observed in the newborn when beta-blockers have been administered until delivery. If the latanoprost/timolol combination is administered until delivery, the newborn should be closely monitored during the first days of life.

Therefore, the latanoprost/timolol combination should not be used during pregnancy (see section Preclinical safety).

Breast-feeding

Beta-blockers are excreted in human milk. However, at therapeutic doses of timolol in eye drops, the amount passing into breast milk is unlikely to be sufficient to produce clinical symptoms of beta-blockers in the infant. To reduce systemic absorption, see section Dosage and administration.

Latanoprost and its metabolites may pass into breast milk.

Therefore, LATANOPROST/TIMOLOL ZENTIVA must not be used in breast-feeding women.

Fertility

Neither latanoprost nor timolol has been shown to have an impact on male or female fertility in animal studies.

The latanoprost/timolol combination has a minor influence on the ability to drive and use machines. Instillation of eye drops may be followed by transient visual disturbances. Until these resolve, patients must not drive or use machines.

For latanoprost, the majority of adverse reactions relate to the eye. During the extension phase of the pivotal studies of the latanoprost/timolol combination, 16 to 20 % of patients developed increased iris pigmentation, which may be permanent. In an open-label clinical trial studying the tolerability of latanoprost over 5 years, 33 % of patients developed increased iris pigmentation (see section Warnings and precautions). Other ocular adverse reactions are generally transient and occur at the time of dose administration. For timolol, the most serious adverse reactions are of a systemic nature, including bradycardia, arrhythmia, congestive heart failure, bronchospasm and allergic reactions.

As with other topically applied ophthalmic medicinal products, timolol is absorbed into the systemic circulation. This may result in adverse reactions similar to those seen with systemic beta-blockers. The incidence of systemic adverse reactions after ophthalmic administration is lower compared with systemic administration. Expected adverse reactions include those observed with the class of ophthalmic beta-blockers.

Treatment-related adverse effects observed in clinical trials with the latanoprost/timolol combination are listed below.

Adverse effects are classified according to their frequency of occurrence, as follows: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1 000, < 1/100).

System/organ	Very common	Common	Uncommon
Nervous system disorders			Headache
Eye disorders	Iris hyperpigmentation	Ocular pain, ocular irritation (including stinging, burning and itching sensation, foreign body sensation)	Corneal disorder, conjunctivitis, blepharitis, ocular hyperaemia, blurred vision, increased lacrimal secretion,
Skin and subcutaneous tissue disorders			Skin rash, pruritus.

Other adverse effects related to the use of either component of the latanoprost/timolol combination have been reported in clinical studies, spontaneous notifications or from the literature.

For latanoprost:

System/organ	Adverse effects
Infections and infestations	Herpetic keratitis.
Nervous system disorders	Dizziness.
Eye disorders	Changes in eyelashes and periorbital hair (increased length, thickness, pigmentation and number of eyelashes), punctate keratitis, periorbital oedema, iritis/uveitis, macular oedema, including cystoid macular oedema, dry eye, keratitis, corneal oedema, corneal ulceration, trichiasis, iris cyst, photophobia, periorbital and eyelid changes following deepening of the eyelid sulcus, eyelid oedema, localised skin reaction at the eyelids, ocular conjunctival pseudopemphigoid+, darker coloration of eyelid skin.
Cardiac disorders	Angina, unstable angina, palpitations.
Respiratory, thoracic and mediastinal disorders	Asthma, aggravation of asthma, dyspnoea.
Gastrointestinal Disorders	Nausea*, vomiting*
Musculoskeletal and systemic disorders	Myalgia, arthralgia.
General disorders and administration site conditions	Chest pain.

+ Potentially attributable to the preservative, benzalkonium chloride

* Frequency of occurrence: uncommon

For timolol:

System/organ	Adverse effects
Immune system disorders	Systemic allergic reactions including anaphylactic reaction, angio-oedema, urticaria, localised or generalised rash, pruritus.
Metabolism and nutrition disorders	Hypoglycaemia.
Psychiatric disorders	Memory loss, insomnia, depression, nightmares, hallucinations.
Nervous system disorders	Cerebrovascular accident, cerebral ischaemia, dizziness, increased signs and symptoms of myasthenia gravis, paraesthesia, headache, syncope.
Eye disorders	Choroidal detachment after filtering surgery (see section Warnings and precautions), corneal erosion, keratitis, diplopia, decreased corneal sensitivity, signs and symptoms of eye irritation (for example: burning, stinging, itching, tearing and redness), dry eye, ptosis, blepharitis, , disorders of the.
Ear and labyrinth disorders	Tinnitus.
Cardiac disorders	Cardiac arrest, heart failure, atrioventricular block, congestive heart failure, chest pain, arrhythmia, bradycardia, oedema, palpitations.
Vascular disorders	Coldness of the extremities, hypotension, Raynaud's phenomenon.
Respiratory, thoracic and mediastinal disorders	Bronchospasm (mainly in patients with pre-existing bronchospastic disease), cough, dyspnoea., .
Gastrointestinal disorders	Abdominal pain, vomiting, diarrhoea, dry mouth, dysgeusia, dyspepsia, nausea.
Skin and subcutaneous tissue disorders	Skin rash, psoriasiform rash, exacerbation of psoriasis, alopecia.
Musculoskeletal and systemic disorders	Myalgia.
Disorders of the reproductive system and breast	Sexual dysfunction, decreased libido.
General disorders and administration site conditions	Asthenia, fatigue.

Phosphate buffers

Cases of corneal calcification have been reported very rarely with the use of phosphate-containing eye drops in patients with significant corneal damage.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reaction via the national reporting system: National Agency for the Safety of Medicines and Health Products (ANSM) and the network of Regional Centres of Pharmacovigilance - Website: www.signalement-sante.gouv.fr.

There is no clinical experience of overdose with the latanoprost/timolol combination.

Symptoms

The symptoms of systemic timolol overdose are: bradycardia, hypotension, bronchospasm and cardiac arrest.

Apart from ocular irritation and conjunctival hyperaemia, no other ocular or systemic adverse effects have been reported in cases of latanoprost overdose.

Treatment

If symptoms of overdose occur, treatment should be symptomatic and supportive. In case of accidental ingestion, the following information may be useful:

Studies have shown that timolol is not easily dialysed. Gastric lavage if necessary.

Latanoprost is extensively metabolised during first hepatic passage. An intravenous infusion of 3 micrograms/kg in healthy volunteers caused no symptoms; however, a dose of 5,5-10 micrograms/kg caused nausea, abdominal pain, dizziness, fatigue, hot flushes and sweating. These effects were mild to moderate and disappeared without treatment within 4 hours of the end of the infusion.

Pharmacotherapeutic group: Ophthalmic beta-blocker - timolol, in combination, ATC code: S01ED51.

Mechanism of action

LATANOPROST/TIMOLOL ZENTIVA combines two components: latanoprost and timolol maleate. These two components reduce elevated intraocular pressure (IOP) through different mechanisms of action. The combined effect results in a further reduction in intraocular pressure compared with that obtained when each component is administered alone.

Latanoprost, a prostaglandin F2alpha analogue, is a selective FP prostanoid receptor agonist that lowers intraocular pressure by increasing the outflow of aqueous humour. The main mechanism of action is increased outflow via the uveoscleral pathway. In addition, an increase in outflow facility (decreased resistance to outflow via the trabecular pathway) has been noted in humans. Latanoprost has no significant effect on aqueous humour production, on the blood-aqueous barrier or on intraocular blood flow. After chronic treatment with latanoprost in monkeys previously subjected to extracapsular lens extraction, no damage to retinal blood vessels was demonstrated by fluorescein angiography. Short-term treatment with latanoprost did not induce fluorescein leakage in the posterior segment of the eye in pseudophakic patients.

Timolol is a non-selective beta-1 and beta-2 adrenergic receptor blocking agent, with no significant intrinsic sympathomimetic activity, no direct cardiac depressant effect and no membrane-stabilising effect. Timolol lowers intraocular pressure by reducing aqueous humour formation in the ciliary epithelium. The precise mechanism of action is not clearly established, but inhibition of the increase in cyclic AMP synthesis caused by endogenous beta-adrenergic stimulation is probable. It has not been shown that timolol significantly affects the permeability of the blood-aqueous barrier to plasma proteins. In rabbits, timolol had no effect on local ocular blood flow after chronic treatment.

Pharmacodynamic effects

Efficacy and safety clinicals

In dose-finding studies, the latanoprost/timolol combination produced a significantly greater reduction in mean diurnal intraocular pressure compared with latanoprost and timolol administered once daily as monotherapy.

In two controlled, double-blind clinical studies of six months' duration, the effect of the latanoprost/timolol combination on intraocular pressure was compared with that of latanoprost and timolol monotherapy in patients with an intraocular pressure of at least 25 mm Hg. After a period of 2 to 4 weeks of timolol treatment (resulting in a mean reduction in intraocular pressure of 5 mm Hg compared with baseline), further mean reductions in diurnal intraocular pressure of 3,1; 2,0 and 0,6 mm Hg were observed, respectively, after 6 months of treatment with the latanoprost/timolol combination (twice daily). The effect was maintained during the open-label extension phase of these studies at 6 months.

Existing data suggest that evening administration may be more effective in lowering IOP than morning administration. However, when deciding between morning or evening administration, the patient's lifestyle and their ability to adhere to treatment should be given sufficient consideration.

It should be borne in mind that if efficacy with the fixed combination is insufficient, study results show that concomitant use of timolol twice daily and latanoprost 1 times daily may still be effective.

The effect of the latanoprost/timolol combination begins within one hour of administration, and a maximum effect is observed after 6 to 8 hours. With repeated administration, the reduction in intraocular pressure is maintained for up to 24 hours after instillation.

Latanoprost

Absorption

Latanoprost is an inactive isopropyl ester prodrug which becomes biologically active after hydrolysis by corneal esterases to latanoprost acid. The prodrug is well absorbed through the cornea and all of the substance entering the aqueous humour is hydrolysed during passage through the cornea.

Distribution

Clinical studies in humans show that the maximum concentration in the aqueous humour, approximately 15-30 ng/ml, is reached about 2 hours after topical administration of latanoprost alone. After topical administration in monkeys, latanoprost is distributed mainly to the anterior segment, the conjunctiva and the eyelids.

The latanoprost acid has a plasma clearance of 0,40 l/h/kg and a low volume of distribution of 0,16 l/kg, resulting in a short plasma half-life of 17 minutes. After ocular administration, the systemic bioavailability of latanoprost acid is 45%. The latanoprost acid has a binding to plasma proteins of 87%.

Biotransformation and elimination

Latanoprost acid is practically not metabolised in the eye. Metabolism is mainly hepatic. Animal studies have shown little or no activity of the main metabolites, the 1, 2-dinor and the 1, 2, 3, 4-tetranor, which are mainly eliminated in the urine.

Timolol

Absorption and distribution

The maximum concentration of timolol in the aqueous humour is reached about 1 hour after topical administration of the eye drops. Part of the dose is absorbed systemically and the maximum plasma concentration of 1 ng/ml is reached 10-20 minutes after daily topical administration of one drop in each eye (300 micrograms/day).

Biotransformation

The plasma half-life of timolol is approximately 6 hours. It is extensively metabolised in the liver.

Elimination

Metabolites are excreted in the urine together with unchanged timolol.

Latanoprost/Timolol (50 micrograms/ml + 5 mg/ml)

Pharmacokinetic/pharmacodynamic relationships

No pharmacokinetic interaction between latanoprost and timolol was observed, despite a concentration of latanoprost acid in the aqueous humour 1-4 hours after administration of the latanoprost/timolol combination that was twice that observed with monotherapy.

The ocular and systemic safety profile of each component is well established. No ocular or systemic adverse effects were observed in rabbits treated topically with the fixed combination or with simultaneous administration of latanoprost and timolol eye drops. Pharmacology, genotoxicity and carcinogenicity studies conducted with each of the components revealed no toxic effects in humans. Latanoprost does not impair corneal wound healing in rabbits, whereas this process is inhibited in rabbits and monkeys treated more than once daily with timolol.

For latanoprost, no effect on fertility was observed in male and female rats. No teratogenic potential was detected in rats and rabbits. No embryotoxic effect was observed in rats after intravenous administration of doses up to 250 micrograms/kg/day. However, latanoprost induces embryo-foetal toxicity, characterised by an increased incidence of late resorptions, abortions and a decrease in foetal weight in rabbits at intravenous doses greater than or equal to 5 micrograms/kg/day (approximately 100 times the therapeutic dose). Timolol does not cause any effect on fertility in male or female rats. No teratogenic potential was observed in mice, rats and rabbits.

Studies in vitro showed precipitation when a thiomersal-containing eye drop was mixed with the latanoprost/timolol combination. If such medicinal products are used concomitantly with LATANOPROST/TIMOLOL ZENTIVA, the drops must be administered at an interval of at least five minutes.

2 years.

After first opening of the bottle: to be stored for a maximum of 28 days.

Storage conditions after first opening of the bottle: store at a temperature not exceeding 25°C.

Before opening, store in a refrigerator (between 2°C and 8°C).

Store the vial in the outer carton in order to protect from light.

Storage conditions after first opening of the bottle: see section Shelf life.

For handling instructions, see the leaflet.

Any unused product or waste must be disposed of in accordance with the regulations in force.

List I

Marketing authorisation (AMM)

CIP 3400926826765 (Fl/2,5ml). CIP 3400926826826 (3Fl/2,5ml).

Price:

7,32 euros (Fl/2,5ml). 19,57 euros (3Fl/2,5ml).

Social security reimbursement at 65% based on the TFR: 7.32 euros (Bottle/2,5 ml), 19.57 euros (3 Bottles/2,5 ml).
Collection.